Novel targeted contrast agent for early detection of brain metastasis: from animal to patient stage 2

Metastasis is the spread of cancer from the initial site, e.g. breast or lung, to a secondary or different part of the body. Metastasis to the brain is one of the most feared complications of cancers such as breast and lung, as it is rarely detected at a stage when it can be treated, and life expectancy once diagnosed is generally only a few months.

Magnetic resonance imaging (MRI) is widely used for diagnosing brain tumours (cancer). These MRI methods use so-called contrast agents, which can be thought of as dyes that alter the intensity or brightness of the images in the areas where they are present. Until now the contrast agents used in cancer diagnosis have needed major damage to the brain blood vessels to occur before their accumulation within the tumour can be seen in the images. As a result, these methods are only able to detect tumours that are well established, and treatments that might have been successful at earlier stages do not work because the disease is too far advanced. To overcome this problem, we have been developing a new type of MRI contrast agent that does not need to accumulate within the tumour via leaky blood vessels. Instead these contrast agents will bind to the surface of the blood vessels that is directly in contact with the blood when certain molecules are present on the vessels.

We have found that the levels of a particular molecule called VCAM-1 are increased on blood vessels that are closely associated with early metastases in the brain. This VCAM-1 expression occurs long before damage to the blood vessels. Using a contrast agent that will bind to VCAM-1, we believe that we have found a way to detect early brain metastases when they cannot otherwise be seen. Under our current MRC DPFS award we have converted our VCAM-1-targeted contrast agent into a form that can be used in humans. We have verified binding of this humanised agent to the target human molecule and will soon start in-depth testing of the agent for any damaging or toxic effects in the body that would prevent its use in man.

Under the current application, therefore, we propose to manufacture the humanised contrast agent to the levels required for human use and to obtain the ethical and regulatory approvals required for human trials. When these approvals are in place, we will undertake a Phase I/IIa clinical trial in cancer patients with known brain metastases. The primary aim of this study will be to assess safety, but it will be designed such that we can also obtain preliminary information as to how effective the contrast agent is in detecting metastases in the brain.

We believe that our approach will greatly improve our ability to diagnose brain metastases in the early stages and, as a result, change the way in which patients with this devastating disease are treated and managed.

Metastasis to the brain is one of the most feared complications of systemic cancers, and prognosis is poor. Magnetic resonance imaging (MRI) is widely used for diagnosis of brain cancer, but the techniques are sensitive to late-stage disease when therapeutic potential is limited. Development of targeted MRI contrast agents, which detect specific molecules expressed early in disease, will overcome this limitation. We have demonstrated that our new contrast agent, targeting the endovascular adhesion molecule VCAM-1, enables detection of micrometastases in mouse brain when this pathology is otherwise undetectable. Our current DPFS award is funding us to create a fully humanised and biodegradeable version of our contrast agent, undertake toxicology and scale up the synthetic protocol. We now seek funding for cGMP synthesis of the agent, acquisition of regulatory and ethical approval and a Phase I/IIa trial in solid cancer patients with known brain metastases. In addition to obtaining safety and pharmacokinetic information, we will obtain some preliminary efficacy data thus maximising value of this Phase I/IIa trial.

The primary beneficiaries of this research are cancer patients at high risk of brain metastasis. A significant proportion of all cancer patients will suffer metastatic spread to the brain. Most brain metastases originate from lung (40-50%), breast (15-25%), melanoma (5-20%), and kidney (5-10%), although the primary site remains unknown in up to 15% of patients.

We anticipate two modes of screening with huVCAM-mMPIO:
(a) Screening at time of primary cancer diagnosis, which will
(i) confirm curative potential of radical therapy for primary when BM are absent,
(ii) enable radical treatment of primary and BM when efficacy is greatest,
(iii) enable decision towards palliative care, when BM are untreatable, improving quality of life.

(b) Periodic screening following treatment of the primary cancer, which will
(i) enable tailored treatment of BM when efficacy is greatest,
(ii) enable decision to palliative care when BM are untreatable,
(iii) prevent unnecessary and debilitating prophylactic treatments when BM are absent.

Refining and increasing management options will increase QALYs overall and reduce costs compared to current gadolinium-based diagnosis. Almost all MRI investigations for brain tumors involve contrast, and we expect ~100,000 UK patients p.a. (~2.5m worldwide) to benefit from huVCAM-mMPIO use. The timescale to the point of patient benefit is likely to be 3-5 years; the current proposal to end of Phase I/IIa trial is 3 years and, if successful, we would anticipate running a full Phase IIb trial soon after that. In this Phase II trial, we would link huVCAM-mMPIO diagnosis of brain metastasis to intervention (e.g. radiotherapy, radiosurgery/surgery), in order to determine efficacy of earlier diagnosis/treatment in limiting symptoms.

Although a limitation to chemotherapy in brain metastases is poor blood-brain barrier (BBB) penetrability, a new generation of therapeutics are in development that circumvent this problem. For example, GRN1005 an LRP-directed peptide-drug conjugate is designed to deliver cytotoxic drug across the intact BBB by exploiting a native transport mechanism. GRN1005 is currently in Phase II trial in breast cancer patients with brain metastases. Similarly, Vorinostat, a histone deactylase inhibitor, has been shown to cross the intact BBB, and is currently in Phase I trial in combination with radiotherapy for the treatment of brain metastases. If successful, such therapeutics could greatly benefit from earlier diagnosis.

At the same time there are many other diseases, both neurological and systemic, with an inflammatory component and for which we anticipate our approach will have clinical application. Moreover, our mMPIO can be targeted with a range of ligands, in addition to our huVCAM antibody. Thus, the production of biocompatible mMPIO, as proposed here, provides a platform for multiple targeting applications across numerous diseases. We expect these additional applications to include multiple sclerosis, atherosclerosis, inflammatory bowel disease, placental inflammation, primary cancers, other secondary cancers, traumatic head injury and transplant rejection. In each of these cases, we have been approached by medical experts in these fields with a view to testing the technology. Once our huVCAM-mMPIO agent has successfully completed the proposed Phase I/IIa trial we will re-engage with these experts and others through the consortium's wide range of expertise (cardiovascular medicine, neurological disease, oncology) with a view to wider clinical application of the agent. It should be noted that RC, Professor of Cardiovascular Medicine and Clinical Director of the Oxford Acute Vascular Imaging Centre, is PI/Co-I of several Phase II trials of drugs targeting vascular inflammation with MRI outputs. Thus, he is ideally placed to translate clinically in these areas.